original article
Annals of Oncology 20: 674–680, 2009 doi:10.1093/annonc/mdn680 Published online 29 January 2009
A phase III randomised trial of LV5FU2 1 irinotecan versus LV5FU2 alone in adjuvant high-risk colon cancer (FNCLCC Accord02/FFCD9802) M. Ychou1*, J.-L. Raoul2, J.-Y. Douillard3, S. Gourgou-Bourgade1, R. Bugat4, L. Mineur5, F. Viret6, Y. Becouarn7, O. Bouche´8, E. Gamelin9, M. Ducreux10, T. Conroy11, J.-F. Seitz12, L. Bedenne13 & A. Kramar1 1 CRLC Val d’Aurelle, Montpellier; 2CRLC Euge`ne Marquis, Rennes, France and European University in Brittany; 3CRLC Rene´ Gauducheau, St Herblain; 4CRLC Claudius Re´gaud, Toulouse; 5Clinique Sainte Catherine, Avignon; 6CRLC Antoine Lacassagne, Nice; 7Institut Bergonie´, Bordeaux; 8CH R. Debre´, Reims; 9CRLC Paul Papin, Angers; 10Institut Gustave Roussy, Villejuif; 11CRLC Alexis Vautrin, Vandoeuvre-les-Nancy; 12CH La Timone, Marseille; 13CHU du Bocage, Dijon, France
Received 14 April 2008; revised 22 September 2008; accepted 23 September 2008
Background: This multicenter adjuvant phase III trial evaluated the addition of irinotecan to LV5FU2 in colon cancer patients at high risk of relapse.
original article
Patients and methods: A total of 400 patients with histologically proven primary colon cancer with postoperative N1 detected by occlusion/perforation or N2 were randomised to: A—LV5FU2 [leucovorin 200 mg/m2, 2-h infusion, 5-fluorouracil (5-FU) 400 mg/m2 bolus, 600 mg/m2 22-h continuous infusion, days 1 and 2] or B—LV5FU2 + IRI (irinotecan 180 mg/m2 90-min infusion day 1 + LV5FU2) fortnightly for 12 cycles. Primary end point was disease-free survival (DFS). Results: Median follow-up was 63 months. Significantly more T4 tumours and 15 or more positive lymph nodes were observed in arm B. 5-FU relative dose intensity (RDI) was >0.80 for 94% and 77% in arms A and B, respectively (P < 0.001). Irinotecan RDI was >0.80 for 70% patients. There were more grades 3 and 4 neutropenia in arm B (4% versus 28%, P < 0.001). The 3-year DFS was 60% [95% confidence interval (CI) 53% to 66%] and 51% (95% CI 44% to 58) in arms A and B, respectively. No difference was observed [hazard ratio (HR) = 1.12, 95% CI 0.85–1.47, P = 0.42] even when adjusted for prognostic factors (adjusted HR = 0.98, 95% CI 0.74–1.31, P = 0.92). The 5-year overall survival (OS) was 67% (95% CI 59% to 73%) and 61% (95% CI 53% to 67%) in arms A and B, respectively. Conclusion: Adjuvant LV5FU2 + IRI compared with LV5FU2 alone in patients at high risk of relapse showed no improvement in DFS and OS. Key words: adjuvant chemotherapy, colon cancer, irinotecan
introduction Colorectal cancer (CRC) is the second cause of cancer death with an estimated 254 000 deaths from CRC worldwide in 2000 [1]. In France the overall incidence of CRC is 36 500 new cases per year of which 70% are colon cancer [2]. Since 1996 the standard chemotherapy for patients with stage III colon cancer is monthly 5-fluorouracil (5-FU) combined with leucovorin (LV) for 6 months (Mayo regimen) [3, 4]. Previously developed in metastatic colorectal cancer (MCRC), the semimonthly LV5FU2 regimen has been compared with the monthly 5FULV in the adjuvant setting and showed no statistically significant difference in overall survival (OS) but showed a better safety profile [5]. The combination of *Correspondence to: Prof. M. Ychou, Centre de Recherche et de Lutte contre le Cancer Val d’Aurelle, 208 rue des apothicaires, 34298 Montpellier Cedex 05, France. Tel: +33-4-67-61-30-66; Fax: +33-4-67-61-30-22; E-mail:
[email protected]
irinotecan (IRI) with 5-FU in MCRC has been shown to improve the tumour response rate, progression-free survival and OS when compared with 5-FU alone [6, 7]. In France, at the time we initiated the trial, the regimen combining LV5FU2 and IRI (180 mg/m2) every 2 weeks had just become standard treatment in first-line MCRC. These data provided a background to compare this new combination to the LV5FU2 regimen alone in the adjuvant setting. Considering the higher risk of toxicity, especially diarrhoea, of LV5FU + IRI given after primary tumour surgery, we chose to evaluate this regimen in a stage III population at a particularly high risk of recurrence defined by patients with more than three involved lymph nodes (N2) or N1 detected by perforation or occlusion [3, 8]. The FNCLCC/FFCD intergroup decided to conduct this adjuvant trial to evaluate the addition of irinotecan to LV5FU2 in terms of disease-free survival (DFS), OS and safety in stage III CRC patients at a high risk of relapse.
ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email:
[email protected]
original article
Annals of Oncology
The first results on 3-year DFS were presented at the American Society of Clinical Oncology (ASCO) meeting in 2005 [9]. In this paper, we report the final analysis of the trial in terms of 5-year OS.
patients and methods patient eligibility The eligibility criteria were the following: histologically proven colon cancer with complete resection of primary tumour (R0), nonmetastatic, with highrisk stage III i.e. N2 (more than three positive lymph nodes) or N1 detected by occlusion or perforation. Patients were aged between 18 and 75 years, without another concomitant or previous cancer (except curatively resected skin cancer or in situ cervical carcinoma), with a neutrophil count >2000/ll; platelets >100 000/ll; serum bilirubin 0.90 for 84% and 60% patients in arms A and B, respectively (P < 0.001). The RDI for irinotecan was >0.80 for 70% patients and >0.90 for 56% of patients.
safety Overall, there were more grades 3–4 adverse events in the experimental arm as compared with the control arm. Grades 3– 4 neutropenia (28% versus 4%), febrile neutropenia (3% versus 0%), nausea (13% versus 2%), vomiting (9% versus 1%), diarrhoea (12% versus 6%) and alopecia (10% versus 1%) were more frequent in arm B than in arm A (Table 2). Seven patients experienced grade 4 diarrhoea, four and three patients in arms A and B, respectively. Hand–foot syndrome was observed for 14 patients (7%) (eight patients with grade 1, five patients with grade 2 and one patient with grade 3) in arm A and seven patients (4%) with grade 1 in arm B (P = 0.11). There was one toxic death after two cycles in arm B due to cardiac arrest, medullar aplasia and a subocclusive state. Overall, there were
676 | Ychou et al.
three deaths within 60 days from last infusion in the experimental arm (1.5%) as compared with none in the control arm.
disease-free survival The database was locked on 31 March 2005 for DFS when 84% of the required number of events was reached after a median follow-up of 36 months. Following Independant Data Monitoring Committee (IDMC) recommendations in July 2004, the results were presented at the ASCO meeting in 2005 [9]. At the cut-off date for analysis, 191 events were recorded. The 3-year DFS rates were 60% [95% confidence interval (CI) 53% to 66%] in arm A and 51% (95% CI 44% to 58%) in arm B. No significant difference was observed between the treatment arms [unadjusted hazard ratio (HR) = 1.19, 95% CI 0.90–1.59, P = 0.22]. The database was updated in January 2007 with a median follow-up of 63 months and a total of 203 first event failures were recorded. There were 177 confirmed relapses: locoregional (A/B: 5 and 12), distant (63 and 68) and local and distant (15 and 14). Median survival after relapse was 19.0, 20.4 and 16.8 months in arms A and B, respectively, corresponding to 2-year OS rates of 41% and 36% which were not statistically significant (P = 0.56). Surgery was used for treatment of relapse in 36% of patients, 37% and 34% in arms A and B, respectively.
Volume 20 | No. 4 | April 2009
original article
Annals of Oncology
Table 1. Baseline patient characteristics
Table 2. Maximum NCI-CTC (v2) toxicity grade per patient, % of grade ‡3
LV5FU2 (n = 198) No. of % patients Stratification factors: all randomised patients Age, years 28 Characteristics: all treated patients Gender Male Female Age, years 28 >42 Performance status 0 1 2 Missing Primary site Right colon Transverse colon Left colon Colorectal junction Rectum T stage T1 T2 T3 T4 N stage N0 N1 N2 No. of sampled nodes 4–7
